The hypothalamo-pituitary-adrenal (HPA) axis is the major stress axis in humans and other mammals. A variety of stressors (and multiple other classes of stimuli) cause release of the hormone ACTH (adrenocorticotropic hormone) from the anterior pituitary gland. ACTH enters the systemic circulation and acts on the adrenal cortex to promote synthesis and release of glucocorticoid hormone (the major endogenous glucocorticoid being cortisol in humans and corticosterone in rodents). The glucocorticoids exert a broad spectrum of effects, the main purpose of which is to mobilize energy sources for successful responsiveness and eventual adaptation to the stressor.
Abnormally elevated HPA axis activity in man is associated with the development of a variety of psychiatric disturbances, some of which are stress-related in aetiology. Elevated cortisol levels, which are indicative of HPA axis hyperactivity and loss of normal negative feedback regulatory processes, are a common finding in affective disorders and various other psychiatric disturbances, and are widely utilized as a diagnostic tool (Holsboer et al., Biol. Psych. 1986, 21, 601-611). It is generally considered that dysregulation of the HPA axis is a reflection of enhanced vulnerability and poor adaptation to chronic stress and that chronic stress therefore plays a major role in the development of affective illness (Sperry and Carlson, DSM-IV diagnosis to treatment, 2nd Edition, Taylor & Francis, 1996). This central concept is supported by experimental evidence utilizing animal models of chronic stress, where aberrant HPA function closely resembles that seen in clinical settings (De Goeij et al., Neuroendocrinology, 1991, 53, 150-159; Plotsky and Meaney, Mol. Brain Res. 1993, 18, 195-200).
The major secretagogues for ACTH in humans and rats are CRH (corticotropin releasing hormone) and AVP (arginine vasopressin). Within the HPA axis these peptide hormones are synthesized by the parvocellular neurones of the paraventricular nucleus (PVN) of the hypothalamus. The axons of these neurones project to the external zone of the median eminence, from where the hormone products enter the hypophysial portal system to bathe the corticotrope cells that manufacture ACTH. CRH and AVP act synergistically at the corticotrope to regulate ACTH secretion in both and in man.
The HPA axis is most potently activated by psychological stressors (i.e., those which require a cognitive assessment of the stimulus). The patterns of AVP and CRH release vary as a function of the type of stressor involved. Acute stress, whether physical or psychological, elicits rapid and robust CRH release. For several psychological stressors, however, chronic application elicits enhanced AVP storage in the median eminence, increased mRNA synthesis, and reduction in AVP neurosecretory granules, whereas similar markers of CRH synthesis and release are relatively unaffected. These findings, when considered together with clinical and experimental data indicating that stress enhances the number of PVN neurones co-expressing CRH and AVP, and that brain levels of AVP are elevated in patients suffering from affective disorders, show that AVP plays an important role as an ACTH secretagogue. Further, they show that chronic psychological stress is associated with a shift in emphasis from CRH to AVP-controlled HPA axis activity. Thus AVP plays a pivotal role in the genesis of the HPA hyperactivity documented in affective disorders.
The actions of AVP at the pituitary cortocotrope are mediated by the vasopressin V3 (or V1b) receptor, which is known and has been cloned (human receptor: Sugimoto et al., J. Biol. Chem., 1994, 269, 27088-27092). A report of clinical studies in depressed patients in which blunted ACTH responses to CRH could be restored by concomitant administration of desmopressin (dDAVP, an AVP agonist with V3 affinity) confirms the involvement of the V3 receptor in depression (Scott and Dinan, Life Sciences, 1998, 62, 1985-1988). A study in rodents with non-selective peptide V3 antagonists indicates that the V3 receptor does play a functional role in control of pituitary ACTH release (Bernardini et al., Neuroendocrinology, 1994, 60, 503-508). Vasopressin antagonists are thus utilized to modulate and normalize pituitary ACTH release and subsequent HPA axis dysfunction in CNS disorders which are characterized by abnormal HPA axis negative feedback mechanisms.
Studies have indicated that V3 antagonists may be useful in the treatment of aggressive behavior [see Wersinger et al. Mol. Psychiatry 7, 975-984 (2002); Blanchard et al. Pharmcol. Biochem. Behav. 80, 189-194 (2005); and Wersinger et al. Horm. Behav. 46, 638-645 (2004)]; insomnia in elderly patients [see Kalamatianos et al. J. Neuroendocrinol. 16, 493-501 (2004)]; cancer [see Dahia el al. J. Clin. Endocrim. Metab. 81, 1768-1771 (1996)]; Cushing's Disease [see Perraudin et al. J. Clin. Endocrin. Metab. 80, 2661-2667 (1995)]; pancreatic disease [see Folny el al. Am. J. Physiol. 285, E566-576 (2003)]; and to effect diuresis [see Chen el al. J. Neurosci. Res. 60, 761-766 (2000)].
In addition to the V3 receptor, vasopressin also activates peripheral receptors, i.e., the V1a receptor, predominantly found on liver and vascular tissue and the V2 receptor, predominantly found on kidney tissue. Interaction at these receptors mediates the pressor and antidiuretic actions of AVP.
Whilst there are several non-peptide low-molecular weight antagonists known which are selective for the V1a or the V2 receptor (for a recent review see Freidinger and Pettibone, Medicinal Research Reviews, 1997, 17, 1-16), there are only a small number of non-peptide ligands known with selectivity for the V3 receptor (see for example, WO 01/55130 and WO 04/009585). There exists therefore a need for further non-peptide V3 selective antagonists which are both safe and effective.